Fanconi's Anemia (FA) is a genetic disorder manifesting with typical congenital malformations, childhood onset progressive bone marrow failure and increased cancer risk. 13 genes responsible for FA have been cloned and together constitute the FA/BRCA pathway which functions to maintain genome stability and to ensure stem cell survival. This Program Project will use a multidisciplinary approach to dissecting the molecular pathophysiology of FA and to use this knowledge to enhance therapy for FA, especially small molecule intervention. The clinical disciplines represented by the investigators include pediatrics, medical genetics, hematology and oncology. The scientific areas of expertise include stem cell biology, DNA repair, molecular hematology, zebra fish genetics, mouse genetics, cytogenetics, gene therapy and drug discovery. Core A will use cell-based assays to screen for novel compounds and genes that positively impact the phenotypes of FA cells. New drugs discovered by screening and others derived from insights into pathophysiology will be systematically evaluated in all 3 projects. Project 1 uses zebrafish models of FA, projects 2 and 3 use FA knockout mice as well as pluripotent stem cells from human FA patients. These IPS cells generated by direct reprogramming will be provided by Core C. Cytogenetic abnormalities are a key feature of FA and Core B will provide support in this area. In addition to drug screening the projects will study genetic interactions of the FA/BRCA pathway, work on the non-canonical roles of FA proteins and explore gene repair as a novel approach for gene therapy in the disease.

Public Health Relevance

The significance of this Program Project is multifold in that therapeutic benefits for FA patients are likely. In addition, however, the work will shed light on generally important processes such as the maintenance of hematopoietic stem cells in the face of damage, leukemogenesis and the action of synthetic androgens in stem cells. Furthermore, drugs that benefit bone marrow failure and delay cancer in FA may well useful in other forms of aplastic anemia and cancer.